EDITORIAL
Antinuclear antibodies in neuromyelitis optica: guardians of the brain?
See paper by H. Masuda et al. on page 276.
In the paper by Masuda et al. [1], the authors present data demonstrating that the presence of serum antinuclear antibody (ANA) may be associated with less severe disease activity in patients with neuromyelitis optica (NMO). Specifically, NMO patients who were ANA+ had a significantly lower annual relapse rate compared to NMO patients who were ANA . Interestingly, the presence of ANAs in the serum of multiple sclerosis (MS) patients also associates with less severe disease activity with shorter disease duration and lower disability scores [2]. Whether this phenomenon may apply to other autoimmune diseases of the central nervous system remains to be seen. Routine ANA testing identifies antibodies to nuclear and cytoplasmic antigens in cell lines, such as Hep-2, by fluorescence microscopy or with purified components in an enzyme-linked immunoassay [3]. ANA positive tests are most commonly associated with autoimmune diseases; however, they might also indicate organ diseases such as pulmonary fibrosis, infections or reactivity to medications. An ANA positive test is often followed by examination of the antibody specificities. For example, antibodies directed against Smith antigens, double-stranded DNA and ribosomal P antigens are common in systemic lupus erythematosus (SLE) and anti-histone antibodies are found in drug-induced SLE whereas antibodies to Ro/SSA and La/SSB are common in Sjogren’s syndrome. What makes the Masuda et al. study quite unique is that the presence of ANAs in NMO is associated with decreased disease severity, whereas the presence of anti-double stranded DNA in SLE is associated with increased disease severity [4]. Why might the presence of ANAs lead to such different clinical outcomes? One might suggest that in NMO, if the peripheral compartment is inundated with B cells responding to nuclear antigens, very little space is left in survival niches [5] for plasmablasts producing antibodies against aquaporin-4 (AQ4), a self-antigen that drives NMO pathology [6]. The same concept may also apply to MS; the peripheral compartment is inundated with B cells responding to nuclear anti-
© 2015 EAN
gens, leaving little bandwidth for B cells responding to as yet unidentified antigens that drive MS pathology. One set of experiments that may have substantiated this concept for NMO would be to determine if there is a negative correlation of anti-AQ4 antibody titers with ANA titers (i.e. high anti-AQ4 titers correlate with low ANA titers resulting in higher disease severity). Probing the specificity, affinity and pattern of the ANA antibodies further might also offer insight into the coupling of the ANA and AQ4 B cell responses. The presence of ANAs, however, does not dispose all ANA+ individuals to disease. For example, healthy controls can also be ANA+ but do not develop SLE [3]. It would be interesting to investigate whether healthy controls are also less likely to develop autoimmune diseases of the central nervous system (CNS) such as NMO and MS since they have high ANA titers. If the data in the Masuda paper are correct, it is likely that healthy controls who are ANA+ may have a lower propensity to develop autoimmune diseases of the CNS. In addition, the affinity of antibodies directed against double stranded DNA (one type of ANA) is much lower in healthy controls compared to SLE patients [7]. In fact, it is thought that ANAs are detectable in healthy controls because the affinity for self-antigens is too low to be detected by tolerance mechanisms (yet high enough to detect by ANA assays). Thus, it would also be of interest to investigate the affinity along with the specificity of the ANA subtypes in NMO patients compared to SLE patients and healthy controls. ANAs from MS patients have similar affinities for Hep-2 lysates as type 1 diabetes and rheumatoid arthritis patients [8]. Finally, ANA-reactive B cells may produce cytokines that influence the severity of inflammation in these peripheral and CNS autoimmune diseases. However, it remains unknown whether autoantibody specificity influences the cytokine profile or T cell response. It is tempting to speculate that ANA+ NMO patients may have a propensity to produce regulatory cytokines. Conversely, ANA+ SLE patients may have a propensity to produce pro-inflammatory cytokines.
223
EUROPEAN JOURNAL OF NEUROLOGY
doi:10.1111/ene.12741
224
EDITORIAL
The Masuda et al. findings certainly lay the foundation for such studies to understand the influence of ANA positivity in the pathophysiology of peripheral and CNS autoimmune diseases.
Acknowledgements The author would like to thank Dr Laurie Davis (Rheumatic Diseases Division, UT Southwestern Medical Center) for valuable comments.
Disclosure of conflicts of interest This work was supported by grants from The National Multiple Sclerosis Society. Dr Monson has no other conflicts to disclose.
N. Monsona,b a
Department
of
Neurology
and
Neurotherapeutics,
UT
Southwestern Medical Center, Dallas, TX; and bDepartment of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
(e-mail: [email protected])
References 1. Masuda H, Mori M, Uzawa A, Muto M, Uchida T, Kuwabara S. Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica. Eur J Neurol 2016; 23: 276–281. 2. Szmyrka-Kaczmarek M, Pokryszko-Dragan A, Pawlik B, et al. Antinuclear and antiphospholipid antibodies in patients with multiple sclerosis. Lupus 2012; 21: 412–420. 3. Pisetsky DS. Anti-DNA and autoantibodies. Curr Opin Rheumatol 2000; 12: 364–368. 4. Pan N, Amigues I, Lyman S, et al. A surge in anti-dsDNA titer predicts a severe lupus flare within six months. Lupus 2014; 23: 293–298. 5. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 2013; 13: 118–132. 6. Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009; 66: 617–629. 7. Bynoe MS, Spatz L, Diamond B. Characterization of anti-DNA B cells that escape negative selection. Eur J Immunol 1999; 29: 1304–1313. 8. Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013; 123: 2737–2741.
© 2015 EAN
Antinuclear antibodies in neuromyelitis optica: guardians of the brain?
See paper by H. Masuda et al. on page 276.
In the paper by Masuda et al. [1], the authors present data demonstrating that the presence of serum antinuclear antibody (ANA) may be associated with less severe disease activity in patients with neuromyelitis optica (NMO). Specifically, NMO patients who were ANA+ had a significantly lower annual relapse rate compared to NMO patients who were ANA . Interestingly, the presence of ANAs in the serum of multiple sclerosis (MS) patients also associates with less severe disease activity with shorter disease duration and lower disability scores [2]. Whether this phenomenon may apply to other autoimmune diseases of the central nervous system remains to be seen. Routine ANA testing identifies antibodies to nuclear and cytoplasmic antigens in cell lines, such as Hep-2, by fluorescence microscopy or with purified components in an enzyme-linked immunoassay [3]. ANA positive tests are most commonly associated with autoimmune diseases; however, they might also indicate organ diseases such as pulmonary fibrosis, infections or reactivity to medications. An ANA positive test is often followed by examination of the antibody specificities. For example, antibodies directed against Smith antigens, double-stranded DNA and ribosomal P antigens are common in systemic lupus erythematosus (SLE) and anti-histone antibodies are found in drug-induced SLE whereas antibodies to Ro/SSA and La/SSB are common in Sjogren’s syndrome. What makes the Masuda et al. study quite unique is that the presence of ANAs in NMO is associated with decreased disease severity, whereas the presence of anti-double stranded DNA in SLE is associated with increased disease severity [4]. Why might the presence of ANAs lead to such different clinical outcomes? One might suggest that in NMO, if the peripheral compartment is inundated with B cells responding to nuclear antigens, very little space is left in survival niches [5] for plasmablasts producing antibodies against aquaporin-4 (AQ4), a self-antigen that drives NMO pathology [6]. The same concept may also apply to MS; the peripheral compartment is inundated with B cells responding to nuclear anti-
© 2015 EAN
gens, leaving little bandwidth for B cells responding to as yet unidentified antigens that drive MS pathology. One set of experiments that may have substantiated this concept for NMO would be to determine if there is a negative correlation of anti-AQ4 antibody titers with ANA titers (i.e. high anti-AQ4 titers correlate with low ANA titers resulting in higher disease severity). Probing the specificity, affinity and pattern of the ANA antibodies further might also offer insight into the coupling of the ANA and AQ4 B cell responses. The presence of ANAs, however, does not dispose all ANA+ individuals to disease. For example, healthy controls can also be ANA+ but do not develop SLE [3]. It would be interesting to investigate whether healthy controls are also less likely to develop autoimmune diseases of the central nervous system (CNS) such as NMO and MS since they have high ANA titers. If the data in the Masuda paper are correct, it is likely that healthy controls who are ANA+ may have a lower propensity to develop autoimmune diseases of the CNS. In addition, the affinity of antibodies directed against double stranded DNA (one type of ANA) is much lower in healthy controls compared to SLE patients [7]. In fact, it is thought that ANAs are detectable in healthy controls because the affinity for self-antigens is too low to be detected by tolerance mechanisms (yet high enough to detect by ANA assays). Thus, it would also be of interest to investigate the affinity along with the specificity of the ANA subtypes in NMO patients compared to SLE patients and healthy controls. ANAs from MS patients have similar affinities for Hep-2 lysates as type 1 diabetes and rheumatoid arthritis patients [8]. Finally, ANA-reactive B cells may produce cytokines that influence the severity of inflammation in these peripheral and CNS autoimmune diseases. However, it remains unknown whether autoantibody specificity influences the cytokine profile or T cell response. It is tempting to speculate that ANA+ NMO patients may have a propensity to produce regulatory cytokines. Conversely, ANA+ SLE patients may have a propensity to produce pro-inflammatory cytokines.
223
EUROPEAN JOURNAL OF NEUROLOGY
doi:10.1111/ene.12741
224
EDITORIAL
The Masuda et al. findings certainly lay the foundation for such studies to understand the influence of ANA positivity in the pathophysiology of peripheral and CNS autoimmune diseases.
Acknowledgements The author would like to thank Dr Laurie Davis (Rheumatic Diseases Division, UT Southwestern Medical Center) for valuable comments.
Disclosure of conflicts of interest This work was supported by grants from The National Multiple Sclerosis Society. Dr Monson has no other conflicts to disclose.
N. Monsona,b a
Department
of
Neurology
and
Neurotherapeutics,
UT
Southwestern Medical Center, Dallas, TX; and bDepartment of Immunology, UT Southwestern Medical Center, Dallas, TX, USA
(e-mail: [email protected])
References 1. Masuda H, Mori M, Uzawa A, Muto M, Uchida T, Kuwabara S. Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica. Eur J Neurol 2016; 23: 276–281. 2. Szmyrka-Kaczmarek M, Pokryszko-Dragan A, Pawlik B, et al. Antinuclear and antiphospholipid antibodies in patients with multiple sclerosis. Lupus 2012; 21: 412–420. 3. Pisetsky DS. Anti-DNA and autoantibodies. Curr Opin Rheumatol 2000; 12: 364–368. 4. Pan N, Amigues I, Lyman S, et al. A surge in anti-dsDNA titer predicts a severe lupus flare within six months. Lupus 2014; 23: 293–298. 5. Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 2013; 13: 118–132. 6. Bennett JL, Lam C, Kalluri SR, et al. Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 2009; 66: 617–629. 7. Bynoe MS, Spatz L, Diamond B. Characterization of anti-DNA B cells that escape negative selection. Eur J Immunol 1999; 29: 1304–1313. 8. Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013; 123: 2737–2741.
© 2015 EAN
